Role of IGFBP7 in Diabetic Nephropathy: TGF-β1 Induces IGFBP7 via Smad2/4 in Human Renal Proximal Tubular Epithelial Cells

Abstract

Tubular injury is one of the important determinants of progressive renal failure in diabetic nephropathy (DN), and TGF-β1 has been implicated in the pathogenesis of tubulointerstitial disease that characterizes proteinuric renal disease. The aim of this study was to identify novel therapeutic target molecules that play a role in the tubule damage of DN. We used an LC-MS/MS-based proteomic technique and human renal proximal epithelial cells (HRPTECs). Urine samples from Japanese patients with type 2 diabetes (n = 46) were used to quantify the candidate protein. Several proteins in HRPTECs in cultured media were observed to be driven by TGF-β1, one of which was 33-kDa IGFBP7, which is a member of IGFBP family. TGF-β1 up-regulated the expressions of IGFBP7 mRNA and protein in a dose- and time-dependent fashion via Smad2 and 4, but not MAPK pathways in HRPTECs. In addition, the knockdown of IGFBP7 restored the TGF-β1-induced epithelial to mesenchymal transition (EMT). In the immunohistochemical analysis, IGFBP7 was localized to the cytoplasm of tubular cells but not that of glomerular cells in diabetic kidney. Urinary IGFBP7 levels were significantly higher in the patients with macroalbuminuria and were correlated with age (r = 0.308, p = 0.037), eGFR (r = −0.376, p = 0.01), urinary β2-microglobulin (r = 0.385, p = 0.008), and urinary N-acetyl-beta-D-glucosaminidase (NAG) (r = 0.502, p = 0.000). A multivariate regression analysis identified urinary NAG and age as determinants associated with urinary IGFBP7 levels. In conclusion, our data suggest that TGF-β1 enhances IGFBP7 via Smad2/4 pathways, and that IGFBP7 might be involved in the TGF-β1-induced tubular injury in DN.

The mitochondria-targeted antioxidant MitoQ ameliorated tubular injury mediated by mitophagy in diabetic kidney disease via Nrf2/PINK1

“…[1] Tubular injury plays a critical role in DKD progression, which correlates with renal functional deterioration, a primary change associated with the disease. [2] The pathogenesis of DKD is not clear, but mitochondrial abnormalities largely contribute to its development. [[3], [5]].…”

Insulin-like growth factor binding protein 7 and tissue inhibitor of metalloproteinases-2: differential expression and secretion in human kidney tubule cells

“…Expression has also been reported in proximal tubule cells, but primarily only in response to insults, mitogens, or second messengers (14,20,41,45,62,63). There is a dearth of information regarding IGFBP7 in the kidney, and what is available is contradictory, showing expression in the glomerulus and alternatively in distal and proximal tubule cells (17,35,42,65,72).…”

Increased IGFBP7 Expression Correlates with Poor Prognosis and Immune Infiltration in Gastric Cancer: An Integrated Bioinformatics Analysis

“…It has been reported that ECM components such as collagen, broblasts and their associated signaling molecules contribute to tumor cell proliferation, migration and invasion in various cancers [40,41]. Moreover, IGFBP7 has been reported to regulate epithelial-mesenchylmal transition (EMT) in some solid tumors [12,42,43]. The above results suggest that IGFBP7 and its coexpressed genes may be involved in ECM-related pathways, which would contribute to the utility of IGFBP7 to predict poor prognosis of GC.…”